SENCAR mice are markedly susceptible to two-stage skin carcinogenesis compared to BALB/c mice. Susceptibility is a property of the skin itself and is not due to differences in metabolism of polycyclic aromatic hydrocarbons. Yet by a variety of biological and biochemical parameters SENCAR epidermal cells behave identically to epidermal cells from less sensitive strains. These include in vitro growth kinetics, receptor binding of growth factors and phorbol esters, density and function of Langerhans cells, production of epidermal thymocyte activating factor, and induction of transglutaminase. SENCAR epidermis, however, appears to have a population of constitutively initiated cells which resist normal differentiation signals. These may be embryonic cells which normally disappear near parturition but persist into adulthood in SENCAR mice.